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Review
. 2024 Feb 29:15:1360891.
doi: 10.3389/fphys.2024.1360891. eCollection 2024.

Uridine and its role in metabolic diseases, tumors, and neurodegenerative diseases

Yueyuan Yang  1 , Yahong Ye  2 , Yingfeng Deng  3 , Ling Gao  1
Affiliations
Review

Uridine and its role in metabolic diseases, tumors, and neurodegenerative diseases

Yueyuan Yang et al. Front Physiol. .

Abstract

Uridine is a pyrimidine nucleoside found in plasma and cerebrospinal fluid with a concentration higher than the other nucleosides. As a simple metabolite, uridine plays a pivotal role in various biological processes. In addition to nucleic acid synthesis, uridine is critical to glycogen synthesis through the formation of uridine diphosphate glucose in which promotes the production of UDP-GlcNAc in the hexosamine biosynthetic pathway and supplies UDP-GlcNAc for O-GlcNAcylation. This process can regulate protein modification and affect its function. Moreover, Uridine has an effect on body temperature and circadian rhythms, which can regulate the metabolic rate and the expression of metabolic genes. Abnormal levels of blood uridine have been found in people with diabetes and obesity, suggesting a link of uridine dysregulation and metabolic disorders. At present, the role of uridine in glucose metabolism and lipid metabolism is controversial, and the mechanism is not clear, but it shows the trend of long-term damage and short-term benefit. Therefore, maintaining uridine homeostasis is essential for maintaining basic functions and normal metabolism. This article summarizes the latest findings about the metabolic effects of uridine and the potential of uridine metabolism as therapeutic target in treatment of metabolic disorders.

Keywords: O-GlcNAc; circadian rhythm; diabetes; metabolic diseases; neurodegenerative diseases; obesity; uridine.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Uridine and its metabolism (A). The mechanism of uridine synthesis and catabolism and the role of uridine in the hexosamine biosynthetic pathway and glycogen synthesis (B). Relationship between ATP consumption and uridine. UTP is produced by the phosphorylation of UDP with ATP used as phosphate donor, a decrease in ATP concentration results in decreased phosphorylation of UDP to UTP, leading to increased UDP and uridine-5′-monophosphate (UMP). These changes accelerate the degradation of uracil nucleotides (UTP→UDP→UMP→ uridine). G-6-P: glucose-6-phosphate; F-6-P: fructose-6-phosphate; GlcN:glucosamine; GlcNAc:N-acetyl glucosamine; UDP:uridine-5′-diphosphate; UTP:uridine-5′-triphosphate; PPi:inorganic pyrophosphate; ADP:cytidine -5′-diphosphate; ATP:cytidine -5′-triphosphate.
FIGURE 2
FIGURE 2
Mechanism of uridine involved in thermoregulation. During fasting, uridine is synthesized mainly by adipose tissue, a process that accompanies the breakdown of fat. The elevated plasma uridine is expected to signal to hypothalamus so that the oxygen consumption and body temperature will decrease. After refeeding, plasma uridine level is decreased through bile, which allows the recovery of oxygen consumption and body temperature. Leptin is not necessary for uridine-induced hypothermia, but leptin-deficiency slows down the recovery of body temperature post uridine administration.
FIGURE 3
FIGURE 3
Effect of uridine on disease through O-GlcNAcylation. Uridine can impact diseases by increasing O-GlcNAc of important functional proteins. Current research focuses mainly on diabetes, Alzheimer’s disease, and cancer. Elevated O-GlcNAc levels of specific proteins can worsen blood glucose status by promoting βcell apoptosis, exacerbating insulin resistance, inhibiting glycogen synthesis, promoting gluconeogenesis, among other mechanisms. However, in the short term, it can also promote insulin secretion, partially explaining the differences in the effects of urinary nucleosides on diabetic patients in the short and long term. The typical pathological manifestation of Alzheimer’s disease is hyperphosphorylation of Tau protein and deposition of β-amyloid protein. Supplementation with uridine can provide neuroprotection by increasing O-GlcNAc of Tau protein, reducing Tau phosphorylation, and preventing Tau aggregation. It can also shift the processing of amyloid precursor protein (APP) towards the non-amyloidogenic pathway mediated by α-secretase and away from the amyloidogenic pathway mediated by β-secretase, reducing the production and deposition of β-amyloid protein-induced neurotoxicity. However, high levels of O-GlcNAc can promote tumor development by promoting tumor cell proliferation, inhibiting tumor cell apoptosis, and promoting tumor cell migration. PDX-1:pancreatic and duodenal homeobox-1; NeuroD1:neurogenic differentiation 1; AKT: kinase B; G6PD: Glucose-6-phosphate dehydrogenase; PDK1: phosphoinositide-dependent kinase 1; PFK1: Phosphofructokinase-1; PKM2: pyruvate kinase M2 isoform; IRS: insulin receptor substrate; APP: Amyloid precursor protein; FoxO1:forkhead box O1; HIF-1α:hypoxia-inducible factor 1 α; CREB:cAMP response element-binding protein; Id2:inhibitor of differentiation 2.
FIGURE 4
FIGURE 4
Relationship between uridine and eating behavior, glucose, and lipid metabolism. (A). The role of uridine in a single meal. During fasting, the expression of CAD, a key enzyme in the synthesis of uridine consisting of glutamine-dependent carbamoyl phosphate synthase, aspartate carbamyltransferase and dihydrogen rotamase, in adipose tissue increases, leading to increased uridine synthesis and release into the blood. Uridine diphosphate (UDP) in the central nervous system is synthesized directly dependent on peripheral circulating uridine levels, and increased UDP synthesis stimulates the appetite center to produce hunger and promote eating. Eating promotes bile clearance, which lowers blood uridine levels while increasing uridine concentration in the gallbladder. The decrease in blood uridine concentration reduces UDP synthesis in the central nervous system, leading to a decrease in hunger and cessation of eating. (B). Short-term effects of uridine supplementation on glucose/lipid metabolism. In animal studies, short-term uridine supplementation in high-fat-fed mice promotes insulin secretion and improves glucose tolerance. It can reduce fat accumulation in the liver and alleviate drug-induced fatty liver. It also results in decreased white adipose tissue in multiple locations and weight loss. (C). Long-term effects of uridine supplementation on glucose/lipid metabolism. In animal studies, long-term uridine supplementation in high-fat-fed mice promotes pancreatic beta-cell apoptosis, increases hepatic gluconeogenesis, reduces effective insulin signaling and decreases peripheral utilization of glucose leading to impaired glucose tolerance. Meanwhile, long-term uridine supplementation in mice results in liver fat accumulation and the development of fatty liver.
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References

    1. Agnati L. F., Fuxe K., Eneroth P., Zini I., Härfstrand A., Grimaldi R., et al. (1986). Intravenous uridine treatment antagonizes hypoglycaemia-induced reduction in brain somatostatin-like immunoreactivity. Acta physiol. Scand. 126 (4), 525–531. 10.1111/j.1748-1716.1986.tb07851.x - DOI - PubMed
    1. Akamine T., Kusunose N., Matsunaga N., Koyanagi S., Ohdo S. (2018). Accumulation of sorbitol in the sciatic nerve modulates circadian properties of diabetes-induced neuropathic pain hypersensitivity in a diabetic mouse model. Biochem. biophysical Res. Commun. 503 (1), 181–187. 10.1016/j.bbrc.2018.05.209 - DOI - PubMed
    1. Altaweraqi R. A., Yao S. Y. M., Smith K. M., Cass C. E., Young J. D. (2020). HPLC reveals novel features of nucleoside and nucleobase homeostasis, nucleoside metabolism and nucleoside transport. Biochimica Biophysica Acta (BBA) - Biomembr. 1862 (7), 183247. 10.1016/j.bbamem.2020.183247 - DOI - PubMed
    1. Aulak K. S., Barnes J. W., Tian L., Mellor N. E., Haque M. M., Willard B., et al. (2020). Specific O-GlcNAc modification at Ser-615 modulates eNOS function. Redox Biol. 36, 101625. 10.1016/j.redox.2020.101625 - DOI - PMC - PubMed
    1. Banerjee P. S., Lagerlöf O., Hart G. W. (2016). Roles of O-GlcNAc in chronic diseases of aging. Mol. aspects Med. 51, 1–15. 10.1016/j.mam.2016.05.005 - DOI - PubMed

Grants and funding

This study was supported by National Science Foundation of China (Project # 82270861 to LG), the Fundamental Research Funds for the Central Universities (Project # 2042020kf1079 to LG), the Planned international development Project of Wuhan University (Project # WHU-GJZDZX TS03 to LG).